The development of the skin from intrauterine to extrauterine life is an orchestrated interplay of epidermal proliferation, terminal differentiation, and barrier formation. Failure to construct an epidermal permeability barrier (EPB), which is a life-threatening problem in the majority of premature infants, results in increased transepidermal water loss with concomitant dehydration and electrolyte imbalance, as well as fragile skin. Barrier defects are also believed to contribute to several hereditary and acquired inflammatory skin disorders, such as psoriasis and atopic dermatitis (AD). Thus, understanding the pathways that are controlled by different regulatory proteins (e.g., transcription factors) in skin is the key for the development of effective treatments for the various skin diseases described above, as well as epithelial cell skin cancers, including head and neck squamous cell carcinoma (HNSCC). Chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2 (CTIP2, also known as Bcl11b) is a transcriptional regulatory protein that is highly expressed in skin during mouse development, as well as in proliferating cells of the adult mouse. We have recently discovered that germline deletion of CTIP2 in mice results in a severe skin phenotype characterized by compromised EPB formation, and dramatically reduced epidermal thickness. We have also observed striking upregulation of CTIP2 in several human HNSCC biopsies, in which the level of CTIP2 expression was inversely correlated with the degree of differentiation of the tumor, i.e., poorly differentiated tumors were found to express very high levels of CTIP2 while highly differentiated tumors expressed very little CTIP2. However, the cellular and molecular mechanism underlying the activity of CTIP2 in skin during epidermal homeostasis and barrier formation is not known. Similarly, we do not understand the role of CTIP2 in proliferative events during skin development or in proliferative diseases of adults, such as HNSCC. Lack of this knowledge is a critical problem in our understanding of the biological roles of the CTIP2 in human health and disease. The long-term goal of this laboratory is to elucidate the molecular and cellular mechanisms that underlie the actions of CTIP2 in fetal, neonatal, and adult skin, and in proliferative diseases of the skin, towards the goal of extrapolating to the human situation. Based on the above observations and from the preliminary data, we propose the following three Specific Aims: (1) to elucidate the cellular and molecular mechanism(s) underlying the role of CTIP2 in EPB formation, (2) to elucidate the cellular and molecular mechanism(s) of CTIP2 action in epidermal proliferation/differentiation, and (3) to determine the role of CTIP2 in pathogenesis of head and neck squamous cell carcinoma. The proposed research is innovative because it will, for the first time, reveal the cellular and molecular mechanisms by which CTIP2 regulates skin organogenesis, EPB formation, and tissue homeostasis. We believe that this research will have significant, positive effects on human health because these outcomes will provide an enhanced understanding of regulatory influences on epidermal keratinocyte proliferation, differentiation and EPB formation, which may lead to development of more efficacious treatment paradigms for the human disorders, such as atopic dermatitis, and possibly HNSCC.